1.1 Immediate Reduction of Blood Pressure

Sodium nitroprusside is indicated for the immediate reduction of blood pressure of adult and pediatric patients in hypertensive crises.

1.2 Induction and Maintenance of Controlled Hypotension

Sodium nitroprusside indicated for induction and maintenance of controlled hypotension in adults and children during surgery, to reduce bleeding.

1.3 Treatment of Acute Heart Failure

Sodium nitroprusside is indicated for the treatment of acute heart failure to reduce, left ventricular end-diastolic pressure, pulmonary capillary wedge pressure, peripheral vascular resistance and mean arterial blood pressure.

2.1 Inspection

Inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Sodium nitroprusside should be a clear colorless to red/brown color; do not use if solution is blue, green, or bright red.

2.2 Dosing

Continuously monitor blood pressure in patients receiving sodium nitroprusside. Start infusion of sodium nitroprusside at a rate of 0.3 mcg/kg/min. Evaluate blood pressure for at least 5 minutes before titrating to a higher or lower dose to achieve the desired blood pressure.  The dose may be titrated upward until:

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the desired effect is achieved,

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systemic blood pressure cannot be further reduced without compromising the perfusion of vital organs, or

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the maximum recommended infusion rate of 10 mcg/kg/min has been reached, whichever occurs first. 

In patients with eGFR <30 mL/min/1.73 m2, limit the mean infusion rate to less than 3 mcg/kg/min.  In anuric patients, limit the mean infusion rate to 1 mcg/kg/min.

2.3 Administration

Do not administer other drugs in the same solution with sodium nitroprusside.

Sodium nitroprusside must be delivered by a volumetric infusion pump because small variations in infusion rate can lead to wide, undesirable variations in blood pressure [see Clinical Pharmacology (12.2)].

5.1 Excessive Hypotension

Sodium nitroprusside, can cause excessive hypotension leading to hypoperfusion of vital organs. Hypotension should resolve within 1-10 minutes after discontinuation of the nitroprusside infusion; during these few minutes, it may be helpful to put the patient into a head-down (Trendelenburg) position to maximize venous return. If hypotension persists more than a few minutes after discontinuation, consider other causes.  Elderly patients may be more sensitive to the hypotensive effects of the drug.

5.2 Cyanide Toxicity

Sodium nitroprusside infusions above 2 mcg/kg/min generate cyanide ion (CN¯) faster than the body can normally dispose of it. At the maximum recommended infusion rate of 10 mcg/kg/min, the patient’s ability to buffer CN¯ will be exceeded in less than one hour [see Overdose (10)].

Patients with hepatic dysfunction are more susceptible to cyanide toxicity.

An early manifestation of cyanide toxicity is increasing dosage requirements to maintain blood pressure control. Metabolic acidosis may not be evident for more than an hour after toxic cyanide levels accumulate.

If cyanide toxicity develops, discontinue sodium nitroprusside, and consider specific treatment of cyanide toxicity [see Overdosage (10)].     

5.3 Thiocyanate Toxicity

Most of the cyanide produced during metabolism of sodium nitroprusside is eliminated in the form of thiocyanate. Thiocyanate is mildly neurotoxic (tinnitus, miosis, hyperreflexia) at serum levels of 1 mmol/L (60 mg/L). Thiocyanate is life-threatening when levels reach ~200 mg/L. Therefore, routine monitoring of plasma thiocyanate levels is recommended in patients with normal renal function when cumulative sodium nitroprusside doses exceed 7 mg/kg/day. In patients with eGFR <30 mL/min/1.73 m2, limit the mean infusion rate to less than 3 mcg/kg/min.  In anuric patients, limit the mean infusion rate to 1 mcg/kg/min.

Renal hemodialysis may be used to eliminate thiocyanate in cases of severe toxicity.   

5.4 Methemoglobinemia

Sodium nitroprusside infusions cause conversion of hemoglobin to methemoglobin in a dose-dependent manner.  Methemoglobin binds oxygen more strongly than does hemoglobin, and when methemoglobin levels are elevated, oxygen release from red blood cells in tissue capillaries may be impaired.  However, conversion of methemoglobin back to hemoglobin is normally rapid, and clinically significant methemoglobinemia is infrequent.

Suspect methemoglobinemia in patients who have received >10 mg/kg of sodium nitroprusside and who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO2. Methemoglobinemic blood is chocolate brown, without the expected color change on exposure to air. Methemoglobin levels >10% are considered clinically significant.

When methemoglobinemia is diagnosed, the treatment of choice is 1-2 mg/kg of methylene blue, administered intravenously over several minutes. 

5.5 Increased Intracranial Pressure

Like other vasodilators, sodium nitroprusside can cause increases in intracranial pressure.

5.6 Anemia and Hypovolemia with Anesthesia

When sodium nitroprusside (or any other vasodilator) is used for controlled hypotension during anesthesia, the patient’s capacity to compensate for anemia and hypovolemia may be diminished. If possible, correct pre-existing anemia and hypovolemia prior to administration.

8.1 Pregnancy

Risk Summary

Based on animal data and mechanism of action, sodium nitroprusside may lead to cyanide exposure and potential adverse effects in the fetus [see Clinical Pharmacology (12.3) and Clinical Considerations]. Published post-marketing reports with sodium nitroprusside use in pregnant women are insufficient to inform a drug-associated risk of adverse pregnancy related outcomes [see Data]. There were no animal reproduction studies conducted with sodium nitroprusside during pregnancy.  However, there are published studies in pregnant sheep that demonstrate that nitroprusside crosses the placenta and that fetal cyanide levels were dose-related to maternal levels of sodium nitroprusside [see Data].  Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use and large doses of sodium nitroprusside during pregnancy may result in cyanide toxicity that may be fatal to the fetus.  In the unusual case that there is no appropriate alternative to therapy with sodium nitroprusside for a particular patient, apprise the mother of the potential risk to the fetus [see Warnings and Precautions (5.2)]. 

Data

Human Data

A small number of cases have reported adverse events, including stillbirths, in pregnant women with severe pregnancy-induced hypertension who were treated with sodium nitroprusside.  However, methodological limitations, including small sample size and limited information on sodium nitroprusside dosage and duration of treatment, as well as the cyanide concentration in maternal blood or fetal tissue, preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of sodium nitroprusside during pregnancy.

Animal Data

In three studies in pregnant ewes, nitroprusside was shown to cross the placental barrier. Fetal cyanide levels were shown to be dose-related to maternal levels of nitroprusside. The metabolic transformation of sodium nitroprusside given to pregnant ewes led to fatal levels of cyanide in the fetuses. The infusion of 25 mcg/kg/min of sodium nitroprusside for one hour in pregnant ewes resulted in the death of all fetuses. Pregnant ewes infused with 1 mcg/kg/min of sodium nitroprusside for one hour delivered normal lambs.

8.2 Lactation

Risk Summary

There is no information about the presence of sodium nitroprusside in human milk, the effects on the breastfed infant, or the effects on milk production. Thiocyanate, one of sodium nitroprusside’s metabolites, is present in human milk. It is unclear how long, if ever, levels of thiocyanate in milk are clinically relevant.

8.4 Pediatric Use

Efficacy in the pediatric population was established based on adult trials and supported by the dose-ranging trial (Study 1) and an open label trial of at least 12 hour infusion at a rate that achieved adequate MAP control (Study 2) with pediatric patients on sodium nitroprusside. No novel safety issues were seen in these studies in pediatric patients [see Clinical Studies (14)].

12.1 Mechanism of Action

Sodium nitroprusside interacts with oxyhemoglobin to produce methemoglobin, cyanide, and nitric oxide (NO). NO then reacts with guanylate cyclase in vascular smooth muscle to produce cGMP that reduces intracellular calcium concentrations resulting in relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins. Other smooth muscle (e.g., uterus, duodenum) is not affected. Sodium nitroprusside is more active on veins than on arteries, but this selectivity is much less marked than that of nitroglycerin. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs.

12.2 Pharmacodynamics

In association with the decrease in blood pressure, sodium nitroprusside administered intravenously to hypertensive and normotensive patients produces slight increases in heart rate and a variable effect on cardiac output. In hypertensive patients, moderate doses induce renal vasodilatation roughly proportional to the decrease in systemic blood pressure, so there is no appreciable change in renal blood flow or glomerular filtration rate.

The hypotensive effect of sodium nitroprusside is seen within a minute or two after the start of an adequate infusion, and it dissipates almost as rapidly after an infusion is discontinued. The effect is augmented by ganglionic blocking agents and inhaled anesthetics.

12.3 Pharmacokinetics

Infused sodium nitroprusside is rapidly distributed to a volume that is approximately coextensive with the extracellular space. The drug is cleared by intraerythrocytic reaction with hemoglobin (Hgb), and sodium nitroprusside’s resulting circulatory half-life is about 2 minutes.

The products of the nitroprusside/hemoglobin reaction are cyanmethemoglobin (cyanmetHgb) and cyanide ion (CN¯).

Metabolism

As shown in the diagram below, the essential features of nitroprusside metabolism are:

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one molecule of sodium nitroprusside is metabolized by combination with hemoglobin to produce one molecule of cyanmethemoglobin and four CN¯ ions;

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methemoglobin, obtained from hemoglobin, can sequester cyanide as cyanmethemoglobin;

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thiosulfate reacts with cyanide to produce thiocyanate;

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thiocyanate is eliminated in the urine;

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cyanide not otherwise removed binds to cytochromes; and

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cyanide is much more toxic than methemoglobin or thiocyanate.

Cyanide ion is normally found in serum; it is derived from dietary substrates and from tobacco smoke. CN¯ levels in packed erythrocytes are typically less than 1 μmol/L (less than 25 mcg/L); levels are roughly doubled in heavy smokers.

At healthy steady state, most people have less than 1% of their hemoglobin in the form of methemoglobin. Nitroprusside metabolism can lead to methemoglobin formation. Relatively large quantities of sodium nitroprusside, however, are required to produce significant methemoglobinemia.

At physiologic methemoglobin levels, the CN¯ binding capacity of packed red cells is a little less than 200 μmol/L (5 mg/L). Cytochrome toxicity is seen at levels only slightly higher, and death has been reported at levels from 300 to 3000 μmol/L (8–80 mg/L). A patient with a normal redcell mass (35 mL/kg) and normal methemoglobin levels can buffer about 175 mcg/kg of CN¯, corresponding to a little less than 500 mcg/kg of infused sodium nitroprusside.

Thiocyanate (SCN¯) is a normal physiological constituent of serum, with normal levels typically in the range of 50-250 μmol/L (3-15 mg/L). Clearance of SCN¯ is primarily renal. In renal failure, the half-life can be doubled or tripled.

When thiosulfate is being supplied only by normal physiologic mechanisms, conversion of CN¯ to SCN¯ generally proceeds at about 1 mcg/kg/min. This rate of CN¯ clearance corresponds to steady-state processing of a sodium nitroprusside infusion of slightly more than 2 mcg/kg/min. CN¯ begins to accumulate when sodium nitroprusside infusions exceed this rate.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies assessing sodium nitroprusside’s carcinogenicity and mutagenicity have not been conducted. Similarly, sodium nitroprusside has not been tested for effects on fertility.

13.2 Animal Toxicology and/or Pharmacology

The acute intravenous mean lethal doses (LD50) of nitroprusside in rabbits, dogs, mice, and rats are 2.8, 5.0, 8.4, and 11.2 mg/kg, respectively.